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Endothelins are potent predominantly vasoconstricting agents that act as local autocrine and paracrine mediators. Endothelin-1 is the most potent and sustained vasoconstrictor and pressor substance yet identified. Abnormalities of the endothelin system occur in a range of diseases associated with vasoconstriction, vasospasm, and vascular hypertrophy. ET receptor antagonists were until recently regarded as drugs of great promise in patients with congestive heart failure, pulmonary hypertension and others. The aim of this article is a survey of compounds that affect the endothelin receptors and clinical trials with these agents.

Endothelins are endogenous vasoactive peptides that are considered among the most potent vasoconstrictor substances known. In addition to their vascular effects, endothelins and their receptors have been shown to be present in many organs and share plenty physiological and pathophysiological functions. Sarafotoxins are natural substances from the venom of snakes genus Atractaspis, structurally and pharmacologically near to endothelins. The current minireview focuses on the chemical and molecular aspects of endothelins and sarafotoxins, and their receptors in physiological and pathophysiological processes.

Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamid) o-fluorophophates for rats and mice (i. m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 to 261 micrograms/kg for rats and from 30.5 to 1222 micrograms/kg for mice, respectively. Different routes of administration in one derivative of this group substituted by methyl groups only were compared. The highest toxicity (lowest LD50 value) in intravenous administration (11 micrograms/kg) and the lowest one in percutaneous (1366 micrograms/kg) were found.

Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamido)-fluorophosphates for rats and mice (i.m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 (rats) to 1222 (mice) micrograms/kg. LD50 values at different routes of administration (i.v., i.m., s.c., p.o. and p.c.) for one derivative of this group, 2-dimethylaminoethyl-(dimethylamido)-fluorophosphate, were determined. Depending on the route of administration, LD50 values varied from 11 (i.v.) to 190 (p.o.) micrograms/kg for rats and from 27.6 (i.v.) to 222 (p.o.) micrograms/kg for mice, respectively. Percutaneous toxicity in rats only (LD50 = 1366 micrograms/kg) was determined.

The cholinomimemtic substance 7-methoxyacrine was administered to eight patients, incl. 5 patients with tardive dyskinesias after neuroleptic drugs. In all patients an europhorizing effect was recorded, all five patients with tardive dyskinesias improved markedly after a single dose, in one female patient after repeated administration symptoms of tardive dyskinesia were eliminated. The incidence of side effects is minimal. Based on our modest experience we consider 7-methoxyacrine an important extension of therapeutic possibilities, in particular in tardive dyskinesias. The authors plan to test 7-methoxyacrine also in other indications, in particular in Alzheimer's disease and in side-effects caused by psychopharmaceutical preparations.

A modification for continual monitoring of the blood acetylcholinesterase activity in the rat on an auto analyzer system was described. With using this technique, inhibition of the enzyme in vitro with O-ethyl-S-(2-dimethylaminoethyl)-methylphosphonothioate was determined. Bimolecular rate constant and I50 values were 1.66-10(6) M-1-min-1 and 1.4-10(-8)M, respectively. Rats treated i.m. with 0.043 mg/kg of this compound showed fast and rapid inhibition of the blood acetylcholinesterase after intoxication. The bimolecular rate constant of inhibition in vivo, calculated analogously as that in vitro was 1.37-10(6) M-1-min-1. On the presumption that both rates of inhibition (in vitro and in vivo) are identical, the concentration of organophosphate producing inhibition effect in vivo was 82% of the dose administered.